Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component.
The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2) transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, alpha smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and beta-catenin and p120(ctn) localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, beta-catenin, and p120(ctn) to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers.
Corsino
Patrick E
PE
Department of Pharmacology and Therapeutics, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA.
Davis
Bradley J
BJ
Nørgaard
Peter H
PH
Parker
Nicole N Teoh
NN
Law
Mary
M
Dunn
William
W
Law
Brian K
BK
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008667:Metalloproteins; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D022502:Stress Fibers / Q000648:ultrastructure; D060589:Zyxin; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D007381:Intermediate Filament Proteins; D008667:Metalloproteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D010750:Phosphoproteins; C498285:Zyx protein, mouse; D060589:Zyxin; D051176:beta Catenin; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D000095002:Delta Catenin